Dopamine (D2) receptor antagonists such as haloperidol and chlorpromazine are most commonly used to treat schizophrenia. However, both acute and chronic administration of these drugs can result in the appearance of extrapyramidal side effects (EPS) which, like the therapeutic effects of these drugs, results from blockade of D2 receptors. Therefore, antipsychotic drugs whose mechanism of action does not involve D2 receptor antagonism will be valuable therapeutic agents. A novel approach to the treatment of schizophrenia is the development of sigma antagonists. NOVA has identified potent and selective, orally active sigma agents having antipsychotic properties. The specific aims of the Phase I study are to identify potent and selective compounds exhibiting oral efficacy using two behavioral paradigms thought to predict antipsychotic potential, and to obtain a structure-activity profile on which to base future medicinal chemistry efforts. The ultimate goal of this research is to identify an antipsychotic agent(s), devoid of EPS liability, that is therapeutically superior to currently available antipsychotics. Given the existing lack of suitable treatments for schizophrenia, the identification and development of an antipsychotic drug that is both efficacious and safe will result in both therapeutic and commercial success.